Hydroxyalkane carboxylic acid derivatives and their production

The invention relates to the use of hydroxyalkane carboxylic acid derivatives of general formula I ##STR2## in which n means the numbers 7 to 18,

R 1 represents a hydrogen atom or an acyl group with a maximum of 16 carbon atoms, and

R 2 and R 3 each mean alkyl groups with a maximum of 8 carbon atoms or together an alkylene group with 4 to 8 carbon atoms optionally interrupted by an oxygen atom or a nitrogen atom, for the production of a pharmaceutical agent for local treatment of diseases of the skin and mucous membrane.

In the publication of G. Czichocki et al. (Tensive Detergents 11, 1974, pp. 298-305) 11-hydroxyundecanoic acid diethylamide and 11-hydroxyundecanoic acid dibutylamide are previously described and 16-hydroxyhexadecanoic acid dimethylamide is mentioned in the publication of D.F. Jones et al. (J. Chem. Soc. (C), 1968, pp. 2821-2827). References to the pharmaceutical effectiveness of these substances are not found in the literature.

This invention relates particularly to previously unknown hydroxyalkane carboxylic acid derivatives of general formula Ia ##STR3## in which R 1 , R 2 and R 3 have the meaning mentioned in Formula I, and

means the same meaning as n, provided that it does not mean the number 10, if R 2 and R 3 each represents an ethyl group or each represents an n-butyl group and that it does not mean the number 15, if R 2 and R 3 each represent a methyl group, their production and pharmaceutical agents (especially those for local treatment of diseases of the skin and mucous membrane), which contain these new hydroxyalkane carboxylic acid derivatives.

It is known that numerous diseases of the skin, i.a., are also caused by cornification disorders of the skin, which come about by increased formation and/or a reduced desquamation of horn cells. Thus, according to present knowledge, a cornification disorder of the follicular epithelium is involved in the origin of acne vulgaris and related diseases of the sebaceous follicle, such as, for example, acne estivalis and acne venenata besides an increased sebum production and a colonization of the follicular lumen with Propionibacterium of acne.

Ichthyosiform dermatoses and follicular hyperkeratoses are cornification disorders of the skin. Psoriasis, parapsoriasis diseases of the skin and lichenoid skin diseases are also characterized by a cornification disorder and additionally by inflammatory processes, as well as an increased blood flow and cell infiltrates.

With warts and dermatomycoses, the cornification disorder, besides the microbiological components, is important for the course of the disease.

Such diseases of the skin, linked to cornification disorders, are treated according to the known prior art with keratinolytics, such as, urea, salicylic acid or benzoyl peroxide with glucocorticoids, retinoids and, in the case of acne therapy, with antibiotics administered locally or systemically. The use of these therapeutic agents is limited either because of their limited effectiveness, as in the case of keratolytics, or because of the local toxicity as well as systemic side effects up to teratogenity of the retinoids. For this reason, the therapy possibilities for diseases, which accompany cornification disorders of the skin, so far have been unsatisfactory.

It has now been found that the hydroxyalkane carboxylic acid derivatives of general formula I surprisingly have a marked antiproliferative effect on keratinocytes, so that pharmaceutical agents, which contain these active ingredients, are very suitable for local treatment of diseases of the skin connected with cornification disorders and/or hyperproliferation of the epidermis. These hydroxyalkane carboxylic acid derivatives further show a marked comedolytic, antiinflammatory and antimicrobial effectiveness and have the advantage of a very slight toxicity, so that pharmaceutical agents containing these active ingredients can be used for local treatment of numerous diseases of the skin and mucous membrane of mammals, e.g., humans.

Specifically, such diseases are, for example:

(a) Diseases of the sebaceous glands and related diseases, such as acne vulgaris, acne venenata, special forms of endogenous acne (e.g., acne neonatorum, acne infantum, acne aestivalis, acne excoriee, and gram-negative folliculitis), rosacea, perioral dermatitis, seborrhoic dermatitis, and seborrhoic eczema.

(b) Cornification disorders of the skin, such as, for example, ichthyosiform dermatoses (e.g., ichthyosis vulgaris, sex-linked hereditary ichthyosis, lamellar ichthyosis, epidermolytic ichthyosis, and Conradi's syndrome), follicular hyper-keratoses (such as keratosis pilaris, keratosis punctata, keratosis striata, keratosis senilis, pityriasis rubra pilaris, and dyskeratosis follicularis vegetans (Darier's disease)), or localized hyperkeratoses (such as palmar and plantar hyperkeratoses and palmar and plantar keratoderm).

(c) Psoriasis and parapsoriatic diseases (such as parapsoriasis guttata, parapsoriasis variegata, and parapsoriasis en plaques).

(d) Lichenoid dermatoses (such as lichen ruber planus and lichen simplex chronicus).

(e) Warts (such as verruca vulgaris, verruca planae juvenilis, and plantar warts).

(f) Dermatomycoses (such as tinea pedis or tinea corporis).

(g) Bacterially superinfected eczemas; and

(h) Premalignant diseases of the epidermis, such as, for example, superficial actinic keratoses.

The antiproliferative effect on keratinocytes was determined in vitro as follows:

Primary cultures of neonatal murine keratinocytes are incubated in serum-free medium for 28 hours with the test substances and terminally for 4 hours with methyl-3H thymidine.

The 3H-thymidine incorporation into the DNA of the keratinocytes serves as measure for its proliferation rate. The following results were obtained in this test:

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Test

Number Substance mol/l % inhibition*

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I 11-hydroxyundecanoic

10.sup.-5

30%

acid dimethylamide

10.sup.-4

70%

II 12-hydroxydodecanoic

10.sup.-5

20%

acid dimethylamide

10.sup.-4

85%

III 13-hydroxytridecanoic

10.sup.-5

70%

acid dimethylamide

10.sup.-4

95%

IV 14-hydroxytetradecanoic

10.sup.-5

85%

acid dimethylamide

10.sup.-4

90%

V 13-hydroxytridecanoic

10.sup.-5

91%

acid dipropylamide

10.sup.-4

92%

VI 13-hydroxytridecanoic acid

10.sup.-5

24%

tetramethyleneamide

10.sup.-4

92%

VII 13-hydroxytridecanoic

10.sup.-5

22%

acid (2,4-dimethyl-3-oxa-

10.sup.-4

62%

pentamethylene)-amide

VIII 13-acetoxytridencanoic

10.sup.-5

32%

acid dimethylamide

10.sup.-4

89%

IX 13-(2,2-dimethylpropionyl-

10.sup.-5

86%

oxy)-tridecanoic acid

10.sup.-4

93%

dimethylamide

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*relative to the vehicle control

The comedolytic effecitveness of the hydroxyalkane carboxylic acid derivatives is determined by inducing on the inside of rabbit ears by topical application of 200 microliters of tetradecane, after a 10-day treatment, comedolike changes of the hair follicles with epithelial hyperplasia and horn cell retentions and by topically applying to the sites thus treated for 11 days daily 200 microliters each of a 5% ethanolic solution of the test substance.

Then the treated areas are punched out and the shrinking of the enlarged follicular lumina is determined, which serves as a measure for the comedolytic activity

In this test, a 5% solution of N,N-dimethyl-13-hydroxytridecanoic acid amide shows a 44.5% inhibition relative to the vehicle control.

To determine the antimicrobial effectiveness, suspension cultures of gram-positive bacteria and dermatophyton in the presence of serially diluted test substances are used under the usual conditions. The bacterial growth is tracked by the cloudiness of the cultures and the minimal inhibition concentration and the minimal biocidal concentration are determined. Table 2 shows the results determined in this test.

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Test

Staphylococcus

Staphylococcus

Streptococcus

Propionibacterium

Bacillus

sub-

aureus μg/l

epidermidis μg/l

pyogenes μg/l

acnes μg/l

substilis μg/l

stance

__________________________________________________________________________

I >0.085

>0.340

>0.170

0.680

0.042

0.085

0.170

0.678

0.085

0.340

II 0.040

0.161

0.161

0.322

0.020

0.040

0.161

0.644

0.040

0.161

III >0.076

>0.304

>0.152

>0.304

0.038

0.076

>0.152

>0.607

>0.076

>0.304

IV 0.098

0.196

>0.196

0.392

0.025

0.049

0.196

0.784

0.049

0.196

V 0.053

0.106

0.214

0.214

0.013

0.013

0.106

0.427

0.053

0.214

__________________________________________________________________________

Test

Trichophyton

Trichophyton

Microsporum

Aspergillus

sub-

rubrum μg/l

mentagrophytes μg/l

canis μg/l

niger μg/l

stance

__________________________________________________________________________

I 0.085

0.340

0.085

0.340

0.170

0.340

0.170

0.680

II 0.080

0.322

0.080

0.322

0.080

0.322

0.161

0.644

III 0.076

0.304

0.076

0.304

0.075

0.304

0.304

0.608

IV 0.098

0.392

0.098

0.392

0.098

0.392

>0.186

>0.784

V 0.106

0.427

0.106

0.427

0.106

0.427

0.214

0.427

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I = 14Hydroxy-tetradecanoic aciddimethylamide

II = 13Hydroxy-tridecanoic aciddimethylamide

III = 12Hydroxy-dodecanoic aciddimethylamide

IV = 13Hydroxy-tridecanoic aciddipropylamide

V = 13(2,2-Dimethylpropionyloxy)-tridecanoic aciddimethylamide

The antiinflammatory effectiveness of the hydroxyalkane carboxylic acid derivatives can be determined by the rat's ear test, which is performed as follows.

An edema is induced on the outside of rat ears by topical application of 50 microliters of 5% solution of croton oil in ethanol. At the same time, a 5% solution of the test substances in ethanol is also applied topically, 5 hours after the application the inhibition of the weight increase of the treated ear is determined, which is a measure of the antiinflammatory effectiveness of the compounds. Table 3 shows the results obtained in this test.

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%

Number Substance Inhibition*

______________________________________

I 11-hydroxyundecanoic acid dimethylamide

54

II 12-hydroxydodecanoic acid dimethylamide

31

III 13-hydroxytridecanoic acid dimethylamide

64

IV 14-hydroxytetradecanoic acid

55

dimethylamide

______________________________________

*relative to the vehicle control

To determine the actue toxicity of the substances according to the invention, 100 mg/kg of 13-hydroxytridecanoic acid dimethylamide is applied interperitoneally to white mice, 6 h ours, 24 hours and 7 days after the application the general condition and the differential hemogram of the test animals had not changed noticeably.

In addition to compounds of general formula I, which carry a free hydroxy group, all compounds with an esterified hydroxy group in vivo will show the same effectiveness spectrum, since these esters will be hydrolytically cleaved in the penetration through the skin. The rate of hydrolysis of the esters and the lipophilicity of these compounds (and thus their penetration capability) will be different in different esters, by which it is possible purposefully to change the intensity of the effectiveness and the period of effectiveness of the hydroxyalkane carboxylic acid derivatives.

Suitable as acyl groups for the acyloxyalkane carboxylic acid derivatives of general formula I are those that have 1 to 16, preferably 1 to 8, carbon atoms.

Such acyl groups are, for example, straight-chain or branched alkanoyl groups, cycloalkylcarbonyl groups, cycloalkylalkanoyl groups, benzoyl groups, alkylbenzoyl groups and phenylalkanoyl groups which can be substituted in the usual way, for example, by 1 or 2 hydroxy groups, alkoxy groups (methoxy groups, etc), alkanoyloxy groups (acetoxy groups, etc.) amino groups, halogens or carboxyl groups. As suitable acyls there can be mentioned, for example: the formyl group, the acetyl group, the propionyl group, the butyryl group, the 2-methylpropionyl group, the pentanoyl group, the 2,2-dimethylpropionyl group, the hexanoyl group, the cyclopentylcarbonyl group, the 3-cyclopropylpropionyl group, the octanoyl group, the dodecanoyl group, the benzoyl group, the hydroxyacetyl group, the methoxyacetyl group, the acetoxyacetyl group, the aminoacetyl group, the 3-carboxypropionyl group, the 2-hydroxybenzoyl group, the 2-acetoxybenzoyl group, the 4-methoxyacetyl group, the 4-chlorobenzoyl group, the 4-methylbenzoyl group and the phenylacetyl group.

Because of the research conducted so far and the general principles in the art, it is evident from the fact that not only the already tested hydroxyalkane carboxylic acid derivatives and their esters have the indicated effectiveness spectrum, but that also structural analogs of these substances show a comparable effectiveness. Such structure analogs are hydroxyalkane carboxylic acid derivatives of general formula I with n meaning 7, 8 17, 18 or especially 9 and 10, 15 and 16, hydroxyalkane carboxylic acid derivatives of general formula I with R 2 and/or R 3 (which can be different) meaning an alkyl group with 2 to 8 (preferably 2 to 4) carbon atoms, such as the ethyl group, propyl group, 2-propyl group as well as hydroxyalkane carboxylic acid derivatives of general formula I with R 2 and R 3 meaning an alkylene group with 4 to 8 carbon atoms optionally interrupted with an oxygen atom or a nitrogen atom. Such alkylene groups are preferably groupings, which together with the amide nitrogen form a ring system of partial formula VI: ##STR4## in which R 4 and R 5 independent of one another represent a hydrogen atom or a methyl group and

X symbolizes a carbon-carbon bond, a methylene group, an oxygen atom, an NH group or>N--CH 3 group.

Such ring systems are, for example, the pyrrolidine ring, the piperidine ring, the piperazine ring and the morpholine ring as well as their derivatives carrying methyl or dimethyl substituents, e.g., on a carbon atom.

The new hydroxyalkane carboxylic acid derivatives of general formula Ia (and analogously all those of Formula I) can, for example, be produced according to a process performed under conditions which are familiar to one skilled in the art, wherein

a) a compound of general formula II ##STR5## in which m is 7-18 and R 1 , R 2 and R 3 have the meanings mentioned above, is decarboxylated, or

b) a carboxylic acid of general formula III

R.sub.1 --O--(CH.sub.2).sub.m --COOH (III),

in which m and R 1 have the above-mentioned meanings, is condensed with an amine of general formula IV ##STR6## in which R 2 and R 3 have the above-mentioned meanings, or c) a compound of general formula V ##STR7## in which R 2 and R 3 have the above-mentioned meanings and R 4 represents an alkyl group with up to 6 carbon atoms, is reduced by catalytically activated hydrogen or complex metal hydrides and optionally the esters of general formula Ia are saponified and free alcohols of general formula Ia are esterified.

The process according to the invention according to process variant a can be is performed under conditions, which are usually used for decarboxylation of malonic acid derivatives. The reaction can take place by heating the compounds of formula I to 80° C.-180° C., and the decarboxylation can be performed in the absence of a solvent or in the presence of a high-boiling solvent (such as xylene, chlorobenzene or decaline).

The starting compounds of general formula II necessary for this process variant can be synthesized, for example, as follows: ##STR8##

(In these formulas, n, R 2 and R 3 have the above-named meanings, X represents a halogen atom--e.g., chlorine, bromine or iodine --and R 6 as well as R 7 are lower alkyl groups with up to 4 carbon atoms, preferably methyl groups or ethyl groups.)

The omega-haloalkanols of formula VII used as starting compounds can be esterified, for example, with acetic hydride and then reacted with the malonic acid derivative of general formula IX under the usual conditions of malonic ester condensation (for example, by the malonic acid derivative in an aprotic solvent such as dimethylformamide being converted into the enolate by sodium hydride and the enolate being reacted with halogen compound VIII). The resulting compound of formula X can then be cleaved hydrolytically--for example with bases--and the compounds of formula II are obtained.

The process according to the invention according to process variant b can also take place under conditions known in the art. For example, it can be performed under reaction conditions, as used in the already mentioned publication of G. Czichocki et al.

The process according to the invention according to process variant c can be performed, for example, under conditions which are usually used in the reductive conversion of alkoxycarbonyl groups to hydroxymethyl groups. Thus, basically, it is possible to perform this reaction with catalytically activated hydrogen, but here there is the danger that the amide group will also be reduced at least partially. Very good results are achieved in the reduction with complex metal hydrides, especially sodium borohydride in inert solvents such as tert-butanol and methanol.

Starting compounds necessary for this process variant can be produced from the corresponding dicarboxylic acid diesters of general formula XI as follows: ##STR9##

(In these formulas n, R 2 and R 3 have the above-named meanings and R 8 in each case represents a lower alkyl group with a maximum of 4 carbon atoms--especially the methyl group or the ethyl group.)

The dicarboxylic acid diesters of formula XI can be partially hydrolyzed with bases, for example, barium hydroxide, to the dicarboxylic acid monoesters of formula XII. These can be converted, for example, with thionyl chloride into the acid chlorides of formula XIII, which are reacted with the amines of general formula IV.

Initially it was already explained in detail that an important aspect of this invention is the use of the hydroxyalkane carboxylic acid derivatives of general formula I for the production of a pharmaceutical agent for local treatment of diseases of the skin and mucous membrane.

The production of such pharmaceutical agents to be applied topically is previously known in the art. But, on the other hand, it is also possible to make new preparations matching the special needs of the skin.

Production of such topical preparations takes place in the usual way, e.g., by the active ingredients with suitable additives being converted into the desired application form, such as a solution, a milk, a lotion, a cream, an ointment or a paste. In the preparation thus formulated, the concentration of active ingredient depends on the form of application. Preferably a concentration of active ingredient of 5 to 30% by weight is used.

The milk, lotion or cream (oil/water emulsions) and the ointment (water/oil emulsions) can be produced in the conventional way by use of conventional emulsifiers (Kirk Othmer; Encyclopedia of Chemical Technology, 3rd edition, 1979; John Wiley & Sons, New York, Vol. 8, pages 900-930, and Dr. Ott-Albrecht Neumueller: Roempps Chemie Lexikon, 7th edition, 1973; Franckhsche Verlagshandlung Stuttgart, pages 1009-1013). The waxes, emulsifiers and other additives used for these emulsions are the same as those conventionally used (Dr. Otto-Albrecht Neumueller: Roempps Chemie Lexikon, 7th edition, 1973; Franckh'sche Verlagshandlung Stuttgart, pages 1427 and 1428).

The topical preparation according to the invention can consist of one or two active ingredients, hydrophilic and/or lipophilic additives, fat phase, oil/water emulsifier, aqueous phase and preservatives.

Moisturizers (hydrocomplexes), such as, for example, propylene glycol, glycerol, polyethylene glycols, vital complexes (such as, for example, placenta extracts), enzymes, herbal extracts (such as, for example, hamamelis extract or chamomile extract) or proteins (such as, for example, collagen, can be used as hydrophilic and/or lipophilic additives. Hydrocarbons, for example squalene, petroleum jelly, paraffins or stearin, or waxes, such as, for example, beeswax or animal or vegetable oils, such as olive oil, peanut oil, fine bone oil, almond oil, jojoba oil, lanolin or sunflower oil are suitable as oily phase or fatty phase in the oil/water emulsion. Stearyl alcohol, polyoxyethylene stearate (such as, for example, MYRJ®), complex emulsifiers (such as, for example, Amphoterin®) and sorbitan fatty acid esters (such as, for example, Tween 80®), carboxyvinylpolymers (such as, for example, Carbopol®), fatty alcohols such as, for example, cetyl alcohol, myristyl alcohol or mixed esters (such as, for example, Dehymuls®) are suitable oil/water emulsifiers. The aqueous phase can in addition also contain buffering agents, such as, for example, disodium salt of ethylenediamine-N,N,N',N'-tetraacetic acid and preservatives such as benzoic acid, chlorquinaldol, parabene or benzalkonium chloride.

The emulsion additionally can be mixed with one or two active ingredients and optionally also with aromatic substances, such as, for example, those of the Crematest® series and stirred until they are uniformly distributed.

It is often advantageous to add to the agents according to the invention additionally about 1 to 4% by weight of a keratolytic active substance, such as, for example, salicylic acid or resorcinol, relative to the total weight of the agent.

The agents of this invention will thus be present in a concentration routinely determined and will be applied topically analogously to related preparations such as

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius and unless otherwise indicated, all parts and percentages are by weight.

The entire disclosures of all applications, patents and publications, if any, cited above and below, and of corresponding application Federal Republic of Germany P 39 05 325.3, filed Feb. 17, 1989, are hereby incorporated by reference.

A) Embodiments relating to the production of hydroxyalkane carboxylic acid derivatives